Our long-term aim is to define the mechanisms by which the ovarian steroids (particularly progesterone) regulate the hypothalamic-pituitary-ovarian axis (especially LRF, LH, FSH and ovulation). Specifically, we hope to elucidate the nature of the reacting steroids, their cellular interactions, the role of metabolism and the biochemical regulatory mechanisms involved in these steroid feedbacks at hypothalamic and pituitary levels. The information gained is expected to give new insights into the steroid regulatory mechanisms affecting this axis, which may ultimately provide important information on the biomedical aspects of contraception and reveal new avenues for fertility control. Toward these ends we will pursue during the next year the following lines of integrated research: 1. Determine the role and characteristics of pituitary and neuroendocrine metabolism of progesterone and related progestins (metabolites, enzymes, modulators, etc.). 2. With in vivo studies using injected progestins, elucidate the nature of the sequestered and reacting steroidal compounds; their sites of localization and modulattng factors. 3. Complement and extend the in vivo studies, with in vitro investigations of pituitary and hypothalamus for soluble and particulate (membrane) binding components. Explore the nature and importance of these steroid interactions with neuroendocrine membranes and lipids in mediating some progesterone effects. 4. Examine (in vivo) the biological relevance of the suggested interactions and metabolites (particularly 5 alpha-reduced compounds) to progesterone's effects (especially LH, FSH and ovulation). Clarify the role of these metabolites as active or inactive metabolites. 5. Extend these findings with in vitro studies (tissue culture, etc.) of the mechanisms, subcellular components, and factors involved in the effects of progesterone, its 5 alpha-reduced metabolites, estradiol, and combinations on the release, synthesis and storage of LRF (with extensions perhaps on LH, FSH release).